GBPDC: Gut-Brain in PD Consortium Master Protocol

Consortium for Gut-Brain Communication in Parkinson's Disease Master Protocol

The purpose of this research study is to identify the role that the gut-brain axis, the group of nerves that connect the brain and gut, plays in Parkinson's disease (PD). The National Institute of Diabetes and Digestive and Kidney Diseases is sponsoring this research study.

During this study, specific groups of participants, also known as "cohorts", will be identified based on the severity of their PD. There will also be a cohort enrolling participants who do not have Parkinson's and a cohort enrolling participants that are at risk for developing PD. Each of these cohorts will be compared to the others to assess the differences in the gut-brain connection.

Participants in this study will:

• meet with a medical provider
• answer questionnaires
• give samples of blood, stool, and saliva
• have X-rays taken while swallowing different foods (swallowing study)
• have X-rays taken to see how long it takes markers to move through their colon (colon transit study)
• have a flexible sigmoidoscopy, where a doctor looks inside the lower part of the colon and takes small tissue samples (biopsies) from the mucosa (lining)
• have samples taken of their skin
• have an anorectal manometry and a balloon expulsion test, where a small tube and balloon are placed in the rectum to measure muscle function.

Participation in the study will last up to 24 months (2 years).

The objectives of the master protocol are to establish a common platform that: (1) assures the collection, integration, and analysis of a set of uniformly collected data across all participating centers, and (2) follows the objective of the Gut-Brain Parkinson's Disease Consortium (GBPDC) with the goal "to enhance our understanding of the temporal onset of GI symptoms in PD and changes in gut-brain communication that can be used to leverage the potential role of the GI tract in the pathogenesis and progression of PD and to improve patient diagnosis, care, and outcomes."

Primary Objective

1. To collect prospective cross-sectional and longitudinal participant biospecimens with temporally coordinated evaluations of GI and neurological symptoms and functions to better characterize the phenotype of people with PD versus those without.

Secondary Objectives

1. To elucidate the biological processes and pathways relevant to the role of the GI tract in the pathogenesis and progression of PD.
2. To characterize GI symptoms, pathology, and gut-brain communication in PD to detect early and longitudinal changes in gut function and activity that correspond to the development or progression of PD.

Exploratory Objectives

1. To identify possible novel gut-based biomarkers (functional, molecular, etc.), diagnostic tools, and therapeutic targets.
2. To investigate the impact of neuroimmune interactions and other pathways in the GI tract on gut-brain communication and PD risk.

In conjunction with clinical, social, and environmental characterization, biospecimen collection within the GBPDC master protocol will provide the opportunity to probe and characterize the pathophysiologic underpinnings of the gut-brain axis in PD, refine existing biomarker testing for PD, and identify new biomarkers that could allow early detection of PD or new targets for treatment.

Duke University will serve as the biorepository for the GBPDC. Participants and study site personnel will collect, process, and ship biospecimens according to the GBPDC Biorepository Manual of Procedures using standard kits assembled specifically for the GBPDC master protocol. Biospecimens will be shipped from the study sites to the GBPDC central biorepository at Duke University for accessioning, storage, tracking, and subsequent distribution for use in approved future research. Throughout the conduct of the master protocol, a portion of the biospecimens received by the GBPDC central biorepository will be transferred to the NIDDK biorepository for approved research use. Any biospecimen aliquots remaining at the GBPDC central biorepository at the termination of the GBPDC program will be transferred to the NIDDK biorepository.

Statistical Design This is a prospective, observational, longitudinal cohort study designed to characterize gut-brain communication in Parkinson's Disease. The study employs a longitudinal design, including cross-sectional analyses of baseline data, to evaluate gastrointestinal and neurological functions in participants with PD compared to household controls and a prodromal cohort, as well as comparisons among PD severity subgroups.

Study Design Features:

• Multi-center observational study across 5 GNRCs
• Three participant cohorts: people with PD, people with prodromal features of PD, and household controls. The PD cohort will be further classified as mild, moderate, or severe PD.
• Longitudinal design with assessments at baseline, 6, 12, 18, and 24 months
• Comprehensive biospecimen collection coordinated with clinical assessments
• Household control design where controls are matched to people with PD when available

Inclusion Criteria (All PD Cohorts)

1. Aged ≥21 years old and ≤80 years old
2. Clinical diagnosis of PD as defined by Movement Disorder Society (MDS) PD Criteria
3. Adequate visual, hearing, cognitive, and physical ability
4. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures. Because longitudinal participation is important to the scientific goals of the program, a "best estimate" of interest, commitment, and geographic feasibility for three years will be documented by the enrolling investigator after interview with the potential enrollee

Inclusion Criteria Controls

1. Aged ≥21 years old and ≤80 years old
2. No known or diagnosed neurodegenerative disease
3. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures
4. Resides within the same household as person with PD

Inclusion Criteria Prodromal Cohort

1. Aged ≥21 years old and ≤80 years old
2. Prodromal characteristics are defined by the MDS Research Criteria for PD and include either polysomnography (PSG)-confirmed rapid eye movement sleep behavior disorder (RBD) or possible RBD (questionnaire-based), with hyposmia as defined by the University of Pennsylvania Smell Identification Test (UPSIT) ≤ 15th percentile.

Exclusion Criteria (All Cohorts)

1. Diagnosis of secondary or atypical parkinsonism

2. Laboratory Values:

   1. Hemoglobin (Hgb) <10
   2. Platelets <70,000
   3. Alanine Transaminase (ALT) or Aspartate Aminotransferase (AST) > 2 1/2 times upper limit of normal (ULN)
   4. Moderate or severe renal disease with an estimated glomerular filtration rate (eGFR) <60 mL/min/BSA [body surface area]) calculated using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, or moderate or severe hepatic impairment (alkaline phosphatase [ALP] >2.0 times the ULN and/or total bilirubin >2.0 times the ULN)
   5. Significantly above the normal range for PT/INR/PTT

3. Currently taking anticoagulants that are deemed exclusionary by the investigator for risk of bleeding with sigmoidoscopy procedure

4. Clinically significant cognitive impairment with a Montreal Cognitive Assessment (MOCA) score <22

5. Clinical or laboratory findings consistent with another primary neurodegenerative disease or cognitive disorder other than PD, including but not limited to, frontotemporal lobar disease, Huntington's disease, progressive supranuclear palsy, multisystem atrophy, Creutzfeld-Jakob- Disease, Down's syndrome, cortico-basal degeneration, dementia with Lewy Bodies, Alzheimer's disease, amyotrophic lateral sclerosis, seizure disorder, stroke, or other infectious, metabolic, or systemic disease affecting the central nervous system including, but not limited to, syphilis, present hypothyroidism, present or unaddressed/treated vitamin B12 deficiency, or other screening laboratory abnormalities

6. Suicidality, defined as active suicidal thoughts or ideation within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide

7. Has cancer or has had a malignant tumor within the past 5 years. (Participants with stable untreated prostate cancer or treated/removed cutaneous carcinomas are not excluded.)

8. Any medical condition or systemic disease that, in the Investigator's opinion, may either put the participant at risk because of participation in the study, influence the results or proposed analyses, or impair the participant's ability to fully participate in the study

9. Body mass index (BMI) >35 kg/m2 or body weight <50 kg

10. Participant is currently pregnant, breastfeeding, and/or lactating

11. History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria)

12. History of Covid 19 (SARS-CoV-2) infection within 6 weeks prior to screening.

13. Participants with unresolved symptoms of Covid 19 infection or ongoing cognitive or other deficits attributable to post-Covid 19 that may affect participant safety or interfere with cognitive assessments based on the Investigator's clinical judgment

14. Either ongoing or current participation in another clinical trial with an investigational agent and have taken at least one dose of study medication, unless unblinded on placebo, within 4 weeks prior to the start of screening, or five half-lives of the investigational drug, whichever is greater. The end of a previous investigational trial is the date the last dose of an investigational agent was taken. Participation in other research studies (e.g., observational studies) may be acceptable throughout this study.

15. History of GI surgery. (However, patients with appendicectomy, hemorrhoid surgery, and cholecystectomy will be eligible to participate).

16. Regular use of medication that impacts the intestinal barrier (e.g., NSAID more than 3 times weekly)

17. Has a history of Crohn's disease, ulcerative colitis, and/or other types of colitis (microscopic, lymphocytic, or collagenous colitis). Confirmed diagnosis of inflammatory bowel disease (IBD) and/or, active or uncontrolled IBD symptoms such as diarrhea, bleeding, or severe stomach pain. Treatment for IBD in the past 6 months with medicines such as steroids, biologics, or strong immune-suppressing drugs. Surgery to remove part of the bowel due to IBD. Other long-term gut diseases that cause inflammation, such as celiac disease.